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PKN1 modulates TGF? and EGF signaling in HEC-1-A endometrial cancer cell line.

ABSTRACT: BACKGROUND: The response of cells to TGF? and EGF is mediated by a network of various intracellular regulators. The signaling crosstalk between different regulators is of key importance for tumorigenesis. The crosstalk may explain the modulation of cellular responses to the same regulator by another signaling molecule. As PKN1 - a serine/threonine kinase implicated in tumorigenesis - was identified as potential crosstalk node for TGF? and EGF signaling, the cellular functions that may be affected by PKN1 in a crosstalk of TGF? and EGF were explored. METHODS: To investigate the contribution of PKN1 to TGF? and EGF signaling, transiently PKN1-transfected HEC-1-A endometrial cancer cells were generated and subjected to treatment with TGF?1, EGF, and their combination. Proliferation, apoptosis, invasion, wound healing, and migration assays were performed. The impact of PKN1 on the expression and phosphorylation of intracellular proteins was monitored by immunoblotting. RESULTS: It was demonstrated that PKN1 modulated the responses of HEC-A-1 endometrial cancer cells to TGF?1 and EGF. PKN1 had an inhibitory effect on the stimulation of cell migration, and PKN1 kinase activity was required for the inhibitory effect of TGF? and EGF on cell proliferation and invasiveness. It was observed that phosphorylation of Smad2, FAK, and Erk1/2 correlated with responses of the cells to TGF?1 and EGF. CONCLUSION: PKN1 modulates TGF?- and EGF-dependent regulation of cell proliferation, migration, and invasiveness, and therefore is a component of the network signaling downstream of TGF? and EGF.

SUBMITTER: Attarha S

PROVIDER: S-EPMC4128851 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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PKN1 modulates TGFβ and EGF signaling in HEC-1-A endometrial cancer cell line.

Attarha Sanaz S Saini Ravi Kanth Rao RK Andersson Sonia S Mints Miriam M Souchelnytskyi Serhiy S

OncoTargets and therapy 20140804

<h4>Background</h4>The response of cells to TGFβ and EGF is mediated by a network of various intracellular regulators. The signaling crosstalk between different regulators is of key importance for tumorigenesis. The crosstalk may explain the modulation of cellular responses to the same regulator by another signaling molecule. As PKN1 - a serine/threonine kinase implicated in tumorigenesis - was identified as potential crosstalk node for TGFβ and EGF signaling, the cellular functions that may be ...[more]

PMID: 25120372

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Project description:BACKGROUND:Progesterone resistance is a problem in endometrial carcinoma, and its underlying molecular mechanisms remain poorly understood. The aim of this study was to elucidate the molecular mechanisms of progesterone resistance and to identify the key genes and pathways mediating progesterone resistance in endometrial cancer using bioinformatics analysis. METHODS:We developed a stable MPA (medroxyprogesterone acetate)-resistant endometrial cancer cell subline named IshikawaPR. Microarray analysis was used to identify differentially expressed genes (DEGs) from triplicate samples of Ishikawa and IshikawaPR cells. PANTHER, DAVID and Metascape were used to perform gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and cBioPortal for progesterone receptor (PGR) coexpression analysis. GEO microarray (GSE17025) was utilized for validation. The protein-protein interaction network (PPI) and modular analyses were performed using Metascape and Cytoscape. Further validation were performed by real-time polymerase chain reaction (RT-PCR). RESULTS:In total, 821 DEGs were found and further analyzed by GO, KEGG pathway enrichment and PPI analyses. We found that lipid metabolism, immune system and inflammation, extracellular environment-related processes and pathways accounted for a significant portion of the enriched terms. PGR coexpression analysis revealed 7 PGR coexpressed genes (ANO1, SOX17, CGNL1, DACH1, RUNDC3B, SH3YL1 and CRISPLD1) that were also dramatically changed in IshikawaPR cells. Kaplan-Meier survival statistics revealed clinical significance for 4 out of 7 target genes. Furthermore, 8 hub genes and 4 molecular complex detections (MCODEs) were identified. CONCLUSIONS:Using microarray and bioinformatics analyses, we identified DEGs and determined a comprehensive gene network of progesterone resistance. We offered several possible mechanisms of progesterone resistance and identified therapeutic and prognostic targets of progesterone resistance in endometrial cancer.

Dataset Information

PKN1 modulates TGF? and EGF signaling in HEC-1-A endometrial cancer cell line.

Publications

PKN1 modulates TGFβ and EGF signaling in HEC-1-A endometrial cancer cell line.

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